Substituted benzene compounds as antiproliferative and cholesterol lowering action

ABSTRACT

The invention provides compounds, compositions and methods relating to novel electrophilic aromatic derivatives and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents. The compositions include compounds of the general Formula I:

INTRODUCTION

1. Field of the Invention

The field of the invention is a particular class of substituted benzenederivatives and analogs and their use as pharmacologically active agentscapable of lowering plasma cholesterol levels and inhibiting abnormalcell proliferation.

2. Background

Atherosclerosis is a leading cause of death in the United States. Thedisease results from excess cholesterol accumulation in the arterialwalls, which forms plaques that inhibit blood flow and promote clotformation, ultimately causing heart attacks, stroke and claudication. Aprincipal source of these cholesterol deposits is the low-densitylipoprotein (LDL) particles that are present in the blood. There is adirect correlation between LDL concentration and plaque formation in thearteries. LDL concentration is itself largely regulated by the supply ofactive LDL cell surface receptors, which bind LDL particles andtranslocate them from the blood into the cell's interior. Accordingly,the upregulation of LDL receptor expression provides an importanttherapeutic target.

Lipoprotein disorders have been previously called thehyperlipoproteinemias and defined as the elevation of a lipoproteinlevel above normal. The hyperlipoproteinemias result in elevations ofcholesterol, triglycerides or both, and are clinically important becauseof their contribution to atherosclerotic diseases and pancreatitis.

Lipoproteins are spherical macromolecular complexes of lipid andprotein. The lipid constituents of lipoproteins are esterified andunesterified (free) cholesterol, triglycerides, and phospholipids.Lipoproteins transport cholesterol and triglycerides from sites ofabsorption and synthesis to sites of utilization. Cholesteryl esters andtriglycerides are nonpolar and constitute the hydrophobic core oflipoproteins in varying proportions. The lipoprotein surface coatcontains the polar constituents—free cholesterol, phospholipids, andapolipoproteins—that permit these particles to be miscible in plasma.

Cholesterol is used for the synthesis of bile acids in the liver, themanufacture and repair of cell membranes, and the synthesis of steroidhormones. There are both exogenous and endogenous sources ofcholesterol. The average American consumes about 450 mg of cholesteroleach day and produces an additional 500 to 1,000 mg in the liver andother tissues. Another source is the 500 to 1,000 mg of biliarycholesterol that is secreted into the intestine daily; about 50 percentis reabsorbed (enterohepatic circulation). The rate-limiting enzyme inendogenous cholesterol synthesis is 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase. Triglycerides, which are nonpolar lipidsconsisting of a glycerol backbone and three fatty acids of varyinglength and degrees of saturation, are used for storage in adipose tissueand for energy.

Lipoproteins are classified into groups based upon size, density,electrophoretic mobility, and lipid and protein composition. Very lowdensity lipoproteins (VLDL) are large, triglyceride-rich lipoproteinsthat are synthesized and secreted by hepatocytes. VLDL interacts withlipoprotein lipase in capillary endothelium, and the core triglyceridesare hydrolyzed to provide fatty acids to adipose and muscle tissue.About half of the catabolized VLDL particles are taken up by hepatic LDLreceptors and the other half remain in plasma, becomingintermediate-density lipoprotein (IDL). IDL is enriched in cholesterylesters relative to triglycerides and is gradually converted by hepatictriglyceride lipase to the smaller, denser, cholesterol ester-rich LDL.As IDL is converted to LDL, apolipoprotein E becomes detached, and onlyone apolipoprotein remains, apo B-100.

LDL normally carries about 75 percent of the circulating cholesterol.Cellular LDL uptake is mediated by a glycoprotein receptor molecule thatbinds to apo B-100. Approximately 70 percent of LDL is cleared byreceptor uptake, and the remainder is removed by a scavenger cellpathway using nonreceptor mechanisms. The LDL receptors span thethickness of the cell's plasma membrane and are clustered in specializedregions where the cell membrane is indented to form craters calledcoated pits. These pits invaginate to form coated vesicles, where LDL isseparated from the receptor and delivered to a lysosome so thatdigestive enzymes can expose the cholesteryl ester and cleave the esterbond to form free cholesterol. The receptor is recycled to the cellsurface.

As free cholesterol liberated from LDL accumulates within cells, thereare three important metabolic consequences. First, there is a decreasein the synthesis of HMG-CoA reductase, the enzyme that controls the rateof de novo cholesterol biosynthesis by the cell. Second, there isactivation of the enzyme acyl cholesterol acyl transferase (ACAT), whichesterifies free cholesterol into cholesterol ester, the cell's storageform of cholesterol. Third, accumulation of cholesterol suppresses thecell's synthesis of new LDL receptors. This feedback mechanism reducesthe cell's uptake of LDL from the circulation.

Lipoproteins play a central role in atherosclerosis. This associationwith the most common cause of death in the developed world defines theprincipal clinical importance of the hyperlipoproteinemias. Individualswith an elevated cholesterol level are at higher risk foratherosclerosis. Multiple lines of evidence, including epidemiological,autopsy, animal studies and clinical trials, have established that LDLis atherosclerogenic and that the higher the LDL level, the greater therisk of atherosclerosis and its clinical manifestations. A certaindegree of LDL elevation appears to be a necessary factor in thedevelopment of atherosclerosis, although the process is modified by manyother factors (e.g., blood pressure, tobacco use, blood glucose level,antioxidant level, and clotting factors). Acute pancreatitis is anothermajor clinical manifestation of dyslipoproteinemia. It is associatedwith chylomicronemia and elevated VLDL levels. Most patients with acutepancreatitis have triglyceride levels above 2,000 mg/dL, but a 1983 NIHconsensus development conference recommended that prophylactic treatmentof hypertriglyceridemia should begin when fasting levels exceed 500mg/dL. The mechanism by which chylomicronemia and elevated VLDL levelscause pancreatitis is unclear. Pancreatic lipase may act ontriglycerides in pancreatic capillaries, resulting in the formation oftoxic fatty acids that cause inflammation.

Abundant evidence indicates that treatment of hyperlipoproteinemia willdiminish or prevent atherosclerotic complications. In addition to a dietthat maintains a normal body weight and minimizes concentrations oflipids in plasma, therapeutic agents that lower plasma concentrations oflipoproteins, either by diminishing the production of lipoproteins or byenhancing the efficiency of their removal from plasma, are clinicallyimportant.

The most promising class of drugs currently available for the treatmentof hyperlipoproteinemia or hypercholesterolemia acts by inhibitingHMG-CoA reductase, the rate-limiting enzyme in endogenous cholesterolsynthesis. Drugs of this class competitively inhibit the activity of theenzyme. Eventually, this inhibition leads to a decrease in theendogenous synthesis of cholesterol and by normal homeostaticmechanisms, plasma cholesterol is taken up by LDL receptors to restorethe intracellular cholesterol balance.

Through both the release of precursors of LDL and receptor-mediated LDLuptake from the serum, liver cells play a critical role in maintainingserum cholesterol homeostasis. In both man and animal models, an inversecorrelation appears to exist between liver LDL receptor expressionlevels and LDL-associated serum cholesterol levels. In general, higherhepatocyte LDL receptor numbers result in lower LDL-associated serumcholesterol levels. Cholesterol released into hepatocytes can be storedas cholesteryl esters, converted into bile acids and released into thebile duct, or it can enter into an oxycholesterol pool. It is thisoxycholesterol pool that is believed to be involved in end productrepression of both the genes of the LDL receptor and enzymes involved inthe cholesterol synthetic pathway.

Transcription of the LDL receptor gene is known to be repressed whencells have an excess supply of cholesterol, probably in the form ofoxycholesterol. A DNA sequence in the LDL receptor promoter region,known as the sterol response element (SRE), appears to confer thissterol end product repression. This element has been extensivelyinvestigated (Brown, Goldstein and Russell, U.S. Pat. Nos. 4,745,060 and4,935,363). The SRE can be inserted into genes that normally do notrespond to cholesterol, conferring sterol end product repression of thechimeric gene. The exact mechanism of the repression is not understood.Brown and Goldstein have disclosed methods for employing the SRE in ascreen for drugs capable of stimulating cells to synthesize LDLreceptors (U.S. Pat. No. 4,935,363). It would be most desirable if thesynthesis of LDL receptors could be upregulated at the level of geneexpression.

The upregulation of LDL receptor synthesis at this level offers thepromise of resetting the level of serum cholesterol at a lower, andclinically more desirable, level. Presently, however, there are nocholesterol lowering drugs that are known to operate at the level ofgene expression. The present invention describes methods and compoundsthat act to inhibit directly or indirectly the repression of the LDLreceptor gene, resulting in induction of the LDL receptor on the surfaceof liver cells, facilitating LDL uptake, bile acid synthesis andsecretion to remove cholesterol metabolites and hence the lowering ofLDL-associated serum cholesterol levels.

A number of human diseases stem from processes of uncontrolled orabnormal cellular proliferation. Most prevalent among these is cancer, ageneric name for a wide range of cellular malignancies characterized byunregulated growth, lack of differentiation, and the ability to invadelocal tissues and metastasize. These neoplastic malignancies affect,with various degrees of prevalence, every tissue and organ in the body.A multitude of therapeutic agents have been developed over the past fewdecades for the treatment of various types of cancer. The most commonlyused types of anticancer agents include: DNA-alkylating agents (e.g.,cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, afolate antagonist, and 5-fluorouracil, a pyrimidine antagonist),microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNAintercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormonetherapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drugwould kill cancer cells selectively, with a wide therapeutic indexrelative to its toxicity towards non-malignant cells. It would alsoretain its efficacy against malignant cells even after prolongedexposure to the drug. Unfortunately, none of the current chemotherapiespossess an ideal profile. Most possess very narrow therapeutic indexes,and in practically every instance cancerous cells exposed to slightlysublethal concentrations of a chemotherapeutic agent will developresistance to such an agent, and quite often cross-resistance to severalother antineoplastic agents.

Psoriasis, a common chronic skin disease characterized by the presenceof dry scales and plaques, is generally thought to be the result ofabnormal cell proliferation. The disease results from hyperproliferationof the epidermis and incomplete differentiation of keratinocytes.Psoriasis often involves the scalp, elbows, knees, back, buttocks,nails, eyebrows, and genital regions, and may range in severity frommild to extremely debilitating, resulting in psoriatic arthritis,pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeuticcure exists for psoriasis. Milder cases are often treated with topicalcorticosteroids, but more severe cases may be treated withantiproliferative agents, such as the antimetabolite methotrexate, theDNA synthesis inhibitor hydroxyurea, and the microtubule disruptercolchicine.

Other diseases associated with an abnormally high level of cellularproliferation include restenosis, where vascular smooth muscle cells areinvolved, inflammatory disease states, where endothelial cells,inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.bacteria, trypanosomes, fungi, etc) are also subject to selectiveproliferative control using the subject compositions and compounds.

Accordingly, it is one object of the present invention to providecompounds which directly or indirectly upregulate LDL receptor synthesisat the level of gene expression and are useful in the treatment ofhypercholesterolemia or hyperlipoproteinemia.

A further object of the present invention is to provide therapeuticcompositions for treating said conditions.

A further object of the invention is to provide therapeutic compositionsfor treating pancreatitis.

Still further objects are to provide methods for upregulating LDLreceptor synthesis, for lowering serum LDL cholesterol levels, and forpreventing and treating atherosclerosis.

A further object of the present invention is to provide compounds whichdirectly or indirectly are toxic to actively dividing cells and areuseful in the treatment of cancer, viral and bacterial infections,vascular restenosis, inflammatory diseases, autoimmune diseases, andpsoriasis.

A further object of the present invention is to provide therapeuticcompositions for treating said conditions.

Still further objects are to provide methods for killing activelyproliferating cells, such as cancerous, bacterial, or epithelial cells,and treating all types of cancers, infections, inflarmmatory, andgenerally proliferative conditions. A further object is to providemethods for treating other medical conditions characterized by thepresence of rapidly proliferating cells, such as psoriasis and otherskin disorders.

Other objects, features and advantages will become apparent to thoseskilled in the art from the following description and claims.

SUMMARY OF THE INVENTION

The invention provides methods and compositions relating to novelsubstituted benzene derivatives and analogs and their use aspharmacologically active agents. The compositions find particular use aspharmacological agents in the treatment of disease states, particularlyhypercholesterolemia, atherosclerosis, cancer, bacterial infections, andpsoriasis, or as lead compounds for the development of such agents. Theinvention provides novel methods for treating pathology such ashypercholesterolemia, atherosclerosis, pancreatitis, andhyperlipoproteinemia, including administering to a patient an effectiveformulation of one or more of the subject compositions.

In one embodiment, the invention provides compounds of general FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R⁴, and R⁵ are independently selected from hydrogen, loweralkyl, halogen, OCF₃, CF₃, NO₂, CO₂H, CN, SO₂—N(R⁶)(R⁷), SO₂—R⁸, CO₂—R⁸,and CO—R⁸;

R³ is a leaving group, such as halogen, NO₂, OCF₃, S(O)—Ar, SO₂—R⁸,SO₂—Ar, N₃, N(R⁶)—SO₂—CF₃, N(R⁶)—SO₂—R⁸, N(R⁶)—SO₂—Ar, N(R⁶)—CO—R⁸,N(R⁶)—CO—Ar, N[CO—R⁸]₂, N(R⁸)₃ ⁺, N(R⁸)₂(Ar)⁺, O—SO₂—Ar, O—SO₂—R⁸,O—SO₂—CF₃, O—CO—(R⁸), O—CO—Ar, O—Ar, O—R⁸, and O—CO—CF₃;

Y is a single bond, —O—, —N(R⁹)—, —N(R⁹)—CH₂—, or —CH(R⁹)—;

and Ar is an optionally substituted aryl or heteroaryl group;

wherein R⁶ and R⁷ are independently chosen from hydrogen, lower alkyl,and lower heteroalkyl;

R⁸ is selected from lower alkyl or lower heteroalkyl; and R⁹ is selectedfrom:

hydrogen,

substituted or unsubstituted (C1-C10)alkyl,

substituted or unsubstituted (C1-C10)alkoxy,

substituted or unsubstituted (C3-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkyl,

substituted or unsubstituted (C3-C6)heteroalkenyl,

substituted or unsubstituted (C3-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C5-C7)cycloalkenyl,

substituted or unsubstituted (C5-C7)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryloxy,

substituted or unsubstituted aryl-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,

substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)alkoxy,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C3-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryfoxy-(C2-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryloxy,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4)alkye , and

substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,

wherein, if Y is —N(R⁹)—, then R⁹ and Ar may be connected by a linkinggroup E to give a substituent of the Formula

 wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)heteroalkylene, and the ring formed by R⁹, E, Ar and the nitrogen atomcontains no more than 8 atoms, or preferably R⁹ and Ar may be covalentlyjoined in a moiety that forms a 5- or 6-membered heterocyclic ring withthe nitrogen atom;

with the following provisos:

At least one of the R¹, R², R⁴, and R⁵ groups is other than hydrogen orlower alkyl;

When R¹=R²=R³=R⁴=R⁵=F, then Y is a single bond or —CH(R⁹)—;

When R¹=R²=R³=R⁴=R⁵=Cl, n=2, and Y=—NH—, then Ar is other thanunsubstituted phenyl or unsubstituted p-biphenyl;

When R¹=R²=R³=R⁴=R⁵=Br, n=2, and Y=—NH—, then Ar is other thanunsubstituted phenyl;

When R³=halogen, n=2, Y=—NH— or —N(R⁹)—, and at least one of R¹, R², R⁴and R⁵ is also halogen, then at least one of R¹, R², R⁴ and R⁵ must beother than hydrogen;

When R¹=H, n=2, and Y=—NH—, then at least one of R², R³, R⁴ and R⁵ mustbe a substituent other than chloro;

When R¹=R⁵=H, n=2, and Y=—N(R⁹)—, then at least one of R², R³, and R⁴must be a substituent other than chloro;

When R¹=R⁵=halogen, R²=R⁴=H, n=2, and Y=—N(R⁹)—, then R³ is asubstituent other than chloro or bromo;

When R¹=R²=halogen, R⁴=R⁵=H, n=2, and Y=—N(R⁹)—, then R³ is asubstituent other than chloro or bromo;

When R¹=R⁴=halogen, R²=R⁵=H, and n=2, then R³is a substituent other thanchloro or bromo;

When R¹=R⁵=halogen, R²=R⁴=H, and Y=—O—, then Ar is a ring system otherthan quinolinyl;

When R¹=F, R³=R⁴=Cl, and Y=—NH—, then Ar is a ring system other than1,3,4-thiadiazolyl;

When R¹=R³=F, R⁴=Cl, and Y=—NH— or —O—, then Ar is a ring other thanunsubstituted phenyl;

When R¹=R³=R⁵=Br, and Y=—NH—, then Ar is a ring other than phenylsubstituted by lower-alkyl;

When R¹=R³=R⁵Cl, Y=—NH—, and R⁹=H or methyl, then Ar is a phenyl ringsubstituted by 1-4 groups chosen independently from halogen, OH, OR′,NH₂, NHR′, and NR′R″, wherein R′ and R″ are as defined below;

When R²=R³=R⁴=Cl, Y=—NH—, and R⁹=propargyl, then Ar is an unsubstitutedring or a ring substituted by a group other than trifluoromethyl ornitro;

When R¹=R³=Cl, and Y=—N(R⁹)—, then R² and R⁴ must both be other thanchloro;

When R²=CF₃, R³=Cl, and Y=—N(R⁹)—, then Ar cannot be either a phenylring substituted by trifluoromethyl, nitro, chloro, or lower-alkylgroups, or a 2-benzothiazolyl ring;

When R²=CO₂H or NO₂, R³=Cl, and Y=—N(R⁹)—, then Ar is an unsubstitutedphenyl or phenyl substituted by a substituent other than CO₂H or CO₂R′;

When R¹=NO₂, R³=Cl, and Y=—NH—, then Ar is a ring system other thanphenyl substituted by either Br or NO₂.

Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienylradicals are selected independently from

—H

—OH

—O-(C1-C10)alkyl

═O

—NH₂

—NH-(C1-C10)alkyl

—N[(C1-C10)alkyl]₂

—SH

—S-(C1-C10)alkyl

—halo

—Si[(C1-C10)alkyl]₃

in a number ranging from zero to (2N+1), where N is the total number ofcarbon atoms in such radical.

Substituents for the aryl and heteroaryl groups are selectedindependently from

—halo

—OH

—O—R′

—O—C(O)—R′

—NH₂

—NHR′

—NR′R″

—SH

—SR′

—R′

—CN

—NO₂

—CO₂H

—CO₂—R′

—CONH₂

—CONH—R′

—CONR′R″

—O—C(O)—NH—R′

—O—C(O)—NR′R″

—NH—C(O)—R′

—NR″—C(O)—R′

—NH—C(O)—OR′

—NR″—C(O)—R′

—NH—C(NH₂)═NH

—NR′—C(NH₂)═NH

—NH—C(NH₂)═NR′

—S(O)—R′

—S(O)₂—R′

—S(O)₂—NH—R′

—S(O)₂—NR′R″

—N₃

—CH(Ph)₂

substituted or unsubstituted aryloxy

substituted or unsubstituted arylamino

substituted or unsubstituted heteroarylamino

substituted or unsubstituted heteroaryloxy

substituted or unsubstituted aryl-(C1-C4)alkoxy,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

perfluoro(C1-C4)alkoxy, and

perfluoro(C1-C4)alkyl,

in a number ranging from zero to the total number of open valences onthe aromatic ring system;

and where R′ and R″ are independently selected from:

substituted or unsubstituted (C1-C8)alkyl,

substituted or unsubstituted (C1-C10)heteroalkyl,

substituted or unsubstituted (C2-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkenyl,

substituted or unsubstituted (C2-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C3-C8)heterocycloalkyl,

substituted or unsubstituted (C5-C6)cycloalkenyl,

substituted or unsubstituted (C5-C6)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C2-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryloxy-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C2-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and

substituted or unsubstituted heteroaryloxy-(C1-C4)heteroalkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the Formula—T—C(O)—(CH₂)_(n)—U—, wherein T and U are independently selected from N,O, and C, and n=0-2. Alternatively, two of the substituents on adjacentatoms of the aryl or heteroaryl ring may optionally be replaced with asubstituent of the Formula —A—(CH2)p—B—, wherein A and B areindependently selected from C, O, N, S, SO, SO₂, and SO₂NR′, and p=1-3.One of the single bonds of the new ring so formed may optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the Formula —(CH₂)_(q)—X—(CH₂)_(r)—, where q and rare independently selected from 1-3, and X is selected from O, N, S, SO,SO₂ and SO₂NR′. The substituent R′ in SO₂NR′ is selected from hydrogenor (C1-C6)alkyl.

In another embodiment, the invention provides for the pharmaceutical useof compounds of the general Formula I and for pharmaceuticallyacceptable compositions of compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R⁴, and R⁵ are independently selected from hydrogen, loweralkyl, halogen, OCF₃, CF₃, NO₂, CO₂H, CN, SO₂—N(R⁶)(R⁷), SO₂—R⁸, CO₂—R⁸,and CO—R⁸;

R³ is a leaving group, such as halogen, NO₂, OCF₃, S(O)—Ar, SO₂—R⁸,SO₂—Ar, N₃, N(R⁶)—SO₂—CF₃, N(R⁶)—SO₂—R⁸, N(R⁶)—SO₂—Ar, N(R⁶)—CO—R⁸,N(R⁶)—CO—Ar, N[CO—R⁸]₂, N(R⁸)₃ ⁺, N(R⁸)₂(Ar)⁺, O—SO₂—Ar, O—SO₂—R⁸,O—SO₂—CF₃, O—CO—(R⁸), O—CO—Ar, O—Ar, O—R⁸, and O—CO—CF₃;

Y is a single bond, —O—, —N(R⁹)—, —N(R⁹)—CH₂—, or —CH(R⁹)—;

and Ar is an optionally substituted aryl or heteroaryl group;

wherein R⁶ and R⁷ are independently chosen from hydrogen, lower alkyl,and lower heteroalkyl;

R⁸ is selected from lower alkyl or lower heteroalkyl; and R⁹ is selectedfrom:

hydrogen,

substituted or unsubstituted (C1-C10)alkyl,

substituted or unsubstituted (C1-C10)alkoxy,

substituted or unsubstituted (C3-C6)alkenyl,

substituted or unsubstituted (C2-C6)heteroalkyl,

substituted or unsubstituted (C3-C6)heteroalkenyl,

substituted or unsubstituted (C3-C6)alkynyl,

substituted or unsubstituted (C3-C8)cycloalkyl,

substituted or unsubstituted (C5-C7)cycloalkenyl,

substituted or unsubstituted (C5-C7)cycloalkadienyl,

substituted or unsubstituted aryl,

substituted or unsubstituted aryloxy,

substituted or unsubstituted aryl-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,

substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,

substituted or unsubstituted aryl-(C1-C4)alkyl,

substituted or unsubstituted aryl-(C1-C4)alkoxy,

substituted or unsubstituted aryl-(C1-C4)heteroalkyl,

substituted or unsubstituted aryl-(C3-C6)alkenyl,

substituted or unsubstituted aryloxy-(C1-C4)alkyl,

substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,

substituted or unsubstituted heteroaryl,

substituted or unsubstituted heteroaryloxy,

substituted or unsubstituted heteroaryl-(C1-C4)alkyl,

substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,

substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,

substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,

substituted or unsubstituted heteroaryloxy-(C1-C4) alkyl, and

substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,

wherein, if Y is —N(R⁹)—, then R⁹ and Ar may be connected by a linkinggroup E to give a substituent of the Formula

 wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)heteroalkylene, and the ring formed by R⁹, E, Ar and the nitrogen atomcontains no more than 8 atoms, or preferably R⁹ and Ar may be covalentlyjoined in a moiety that forms a 5- or 6-membered heterocyclic ring withthe nitrogen atom;

with the following provisos:

At least one of the R¹, R², R⁴, and R⁵ groups is other than hydrogen orlower alkyl;

When R¹=R²=R³=R⁴=R⁵=F, then Y is a single bond or —CH(R⁹)—;

When R¹=R²=R³=R⁴=R⁵=Cl, n=2, and Y=—NH—, then Ar is other thanunsubstituted phenyl or unsubstituted p-biphenyl;

When R¹=R²=R³=R⁴=R⁵=Br, n=2, and Y=—NH—, then Ar is other thanunsubstituted phenyl;

When R³=halogen, n=2, Y=—NH— or —N(R⁹)—, and at least one of R¹, R², R⁴and R⁵ is also halogen, then at least one of R¹, R², R⁴ and R⁵ must beother than hydrogen;

When R¹=H, n=2, and Y=—NH—, then at least one of R², R³, R⁴ and R⁵ mustbe other than chloro;

When R¹=R⁵=H, n=2, and Y=—N(R⁹)—, then at least one of R², R³, and R⁴must be a substituent other than chloro;

When R¹=R³=R⁵=Cl, Y=—NH—, and R⁹=H or methyl, then Ar is a phenyl ringsubstituted by 1-4 groups chosen independently from halogen, OH, OR′,NH₂, NHR′, and NR′R″, wherein R′ and R″ are as defined above;

When R¹=R³=Cl and Y=—N(R⁹)—, then R² and R⁴ must both be other thanchloro; and

When R²=CF₃, R³=Cl, and Y=—N(R⁹)—, then Ar cannot be either a phenylring substituted by trifluoromethyl, nitro, chloro, or lower-alkylgroups, or a 2-benzothiazolyl ring.

In yet another embodiment, the present invention provides novel methodsfor the use of the subject pharmaceutical compositions for treatingpathology such as cancer, bacterial infections, psoriasis,hypercholesterolemia, atherosclerosis, pancreatitis, andhyperlipoproteinemia, including administering to a patient an effectiveformulation of one or more of the subject compositions.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION

The term “alkyl” by itself or as part of another substituent means,unless otherwise stated, a straight or branched chain hydrocarbonradical, including di- and multi-radicals, having the number of carbonatoms designated (i.e. C1-C10 means one to ten carbons) and includesstraight or branched chain groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomersof n-pentyl, n-hexyl, 2-methylpentyl, 1,5-dimethylhexyl,1-methyl-4-isopropylhexyl and the like. The term “alkylene” by itself oras part of another substituent means a divalent radical derived from analkane, as exemplified by —CH₂CH₂CH₂CH₂—. A “lower alkyl” is a shorterchain alkyl, generally having six or fewer carbon atoms.

The term “heteroalkyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainradical consisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include —O—CH₂—CH₂—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂—S(O)—CH₃, —O—CH₂—CH₂—CH₂—NH—CH₃, and —CH₂—CH₂—S(O)₂—CH₃. Up totwo heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like.Examples of heterocycloalkyl include 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term “alkenyl” employed alone or in combination with other termsmeans, unless otherwise stated, a stable straight chain or branchedmonounsaturated or diunsaturated hydrocarbon group having the statednumber of carbon atoms. Examples include vinyl, propenyl (allyl),crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by —CH═CH—CH₂—.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or diunsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen andsulfiir atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quartemized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

The term “alkynyl” employed alone or in combination with other termsmeans, unless otherwise stated, a stable straight chain or branchedhydrocarbon group having the stated number of carbon atoms, andcontaining one or two carbon-carbon triple bonds, such as ethynyl, 1-and 3-propynyl, 4-but-1-ynyl, and the higher homologs and isomers.

The term “alkoxy” employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group, as defined above,connected to the rest of the molecule via an oxygen atom, such as, forexample, methoxy, ethoxy. 1-propoxy, 2-propoxy and the higher homologsand isomers.

The terms “halo” or “halogen” by themselves or as part of anothersubstituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The term “aryl” employed alone or in combination with other terms means,unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthyl group. Themaximal number of substituents allowed on each one of these ring systemsis five, seven, and seven, respectively. Substituents are selected fromthe group of acceptable substituents listed above.

The term “heteroaryl” by itself or as part of another substituent means,unless otherwise stated, an unsubstituted or substituted, stable, mono-or bicyclic heterocyclic aromatic ring system which consists of fromfour to ten carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized, and the nitrogen atom(s) mayoptionally be quaternized. The heterocyclic system may be attached,unless otherwise stated, at any heteroatom or carbon atom which affordsa chemically stable structure. The heterocyclic system may besubstituted or unsubstituted with one to four substituents independentlyselected from the list of acceptable aromatic substituents listed above.Examples of such heterocycles include 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl.

The term “lower” used alone or in combination Awith another termindicates that a radical or substituent group contains a total number ofheavy atoms (carbon, oxygen, nitrogen, etc) between one and ten.

A “leaving group” as used herein is a substituent on an aromatic ringthat can be displaced by a heteroatom nucleophile in an aromaticsubstitution or “S_(N)Ar” reaction, particularly by a sulfhydryl groupunder physiological conditions, i.e. within the range of intracellularpH, ionic strength and temperature tolerances. Reactions of the S_(N)Artype proceed in solution through a σ-complex (Meisenheimer complex)which may be an intermediate or a transition state; see, AdvancedOrganic Chemistry, by Jerry March, 2nd Edition, McGraw-Hill, New York:1997, pages 594-595, and references in footnote 2 of Chapter 13. A widevariety of such leaving groups find use in the subject invention.Exemplary suitable leaving groups include: fluoro, chloro, bromo, iodo,nitro, trifluoromethoxy, Ph—S(O)—, azido, CF₃SO₂NH—, PhSO₂NH—,trimethylammonium, PhOSO₂—, and trifluoroacetate. Preferred leavinggroups are at least as thiolate reactive as the para-fluorinesubstituent of the corresponding 2,3,4-trifluorobenezene moietycontaining compound of the invention. Thiolate nucleophile S_(N)Arreactivity is readily determined empirically with the assays describedbelow or as a calculated free energy barrier; see, e.g. Zheng andOmstein (J. Am. Chem. Soc., 1997, 119, 648-655). Briefly, ab initioquantum mechanical calculations including gas phase geometryoptimization in the reaction intermediates and complexes are performed,e.g. at the HF/6-31+G** level of theory using GAUSSIAN 94 (GausssianInc., Pittburg Pa.). The solvation free energy is then calculated fromthe ab initio results using a solvent-effect modeling program (e.g.PS-GVB), and the overall free energy for the S_(N)Ar reaction isobtained by adding the gas phase and solution free energy profiles.

Pharmaceutically acceptable salts of the compounds of Formula I includesalts of these compounds with relatively nontoxic acids or bases,depending on the particular substituents found on specific compounds ofFormula I. When compounds of Formula I contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of compound I with a sufficient amount of the desired base,either neat or in a suitable inert solvent. Examples of pharmaceuticallyacceptable base addition salts include sodium, potassium, calcium,ammonium, organic amino, or magnesium salt, or a similar salt. Whencompounds of Formula I contain relatively basic functionalities, acidaddition salts can be obtained by contacting the neutral form ofcompound I with a sufficient amount of the desired acid, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like gluconic or galactunoric acids and the like(see, for example, Berge, S. M., et al, “Pharmaceutical Salts”, Journalof pharmaceutical Science, 1977, 66, 1-19). Certain specific compoundsof Formula I contain both basic and acidic functionalities that allowthe compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers); the racemates, diastereomers, and individualisomers are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium (³H)or carbon-14 (¹⁴C). All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

Illustrative examples of compounds and pharmaceutical compositions ofthe subject pharmaceutical methods include:

4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobezene;

4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-[(3-Chloro-4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene;

2,3,4-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

3,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

4-Fluoro-1-[(4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;

2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;

4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethylsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethylsulfonamido-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethylsulfonamido-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-(Diacetylamino)-2,3-difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-5-nitrobenzene;

2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2,4,5,6-Tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulphenyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;

2,3,4,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzene;

2-Fluoro-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;

2-Fluoro-5-[(3,4-dimethoxyphenyl)methylsulfonyl]benzonitrile;

2,3,4-Trifluoro-5-[(4-dimethylaminophenyl)sulfonyl]benzoic acid, ethylester;

2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)sulfenyl]benzoic acid,ethyl ester;

1-Chloro-4-[(4-methoxyphenyl)methylsulfonyl]-2-nitrobenzene;

1-Chloro-4-[(4-dimethylaminophenyl)sulfonyl]-2-nitrobenzene;

2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;

4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene; and

4,5-Difluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;

Compounds of general Formula I, or a pharmaceutically acceptable saltthereof, are preferred in which:

R¹, R², R⁴, and R⁵ are independently selected from hydrogen, F, Cl, Br,OCF₃, CF₃, SO₂-(lower-alkyl), NO₂, CN, and SO₂—N(R⁶)(R⁷);

R³ is halogen or OCF₃;

n=2;

Y is a single bond, —N(R⁹)—, or —CH(R⁹)—;

Ar is an optionally substituted aryl or heteroaryl group;

and R⁶, R⁷ and R⁹ are independently chosen from hydrogen, lower alkyl,and lower heteroalkyl.

Also preferred are compounds of Formula I in which there is no linkinggroup E between R⁹ and Ar.

Most preferred are compounds of Formula I in which:

R¹, R², R⁴, and R⁵ are independently selected from hydrogen, F, Cl, Br,OCF₃, CF₃, NO₂, and CN;

R³ is halogen or OCF₃;

Y is —NH—;

n=2;

Ar is an optionally substituted aryl group;

R⁶ and R⁷ are independently selected from lower-alkyl;

R⁹ is hydrogen;

and there is no linking group E between R⁹ and Ar.

Preferred compounds and compositions of this embodiment of the inventionhave specific pharmacological properties. Examples of most preferredcompounds and compositions of this embodiment of the invention include:

4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene; 2 54-Fluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;

2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;

5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-fluorobenzonitrile;

4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4,5-Difluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;

2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2,3,4-Trifluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,3,4-Trifluoro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,4,5,6-Tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2,4,5,6-Tetrafluoro-3-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)aminosulfonyl]benzoicacid, ethyl ester;

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]benzene;

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)arninosulfony]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4,5,6-trifluoro-2-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,4-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,4-trifluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene; or

3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene.

1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Chloro-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;

2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.

2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;

2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl ester;

2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid, ethylester;

1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

1-Chloro-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Chloro-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

1-Chloro-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Bromo-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Bromo-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Bromo-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Bromo-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;

1-Bromo-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;

2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.

2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;

2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;

2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl ester;

2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Bromo-5-[(3,4-dimethoxy phenyl)aminosulfonyl]benzoic acid, ethylester;

2-Bromo-5-[(4-dimethylamxinophenyl)aminosulfonyl]benzoic acid, ethylester;

1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl) aminosulfonyl]benzene,

1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

1-Bromo-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

1-Bromo-2,3,6-trifluoro-4-[(3,4-dimethoxypheny l)aminosulfonyl]benzene;

4-Trifluoromethoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethoxy-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;

4-Trifluoromethoxy-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;

2-Trifluoromethoxy-5-[(4-methoxyphenyl) aminosulfonyl]benzonitrile;

2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;

2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.

2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;

2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;

2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethylester;

2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoicacid, ethyl ester;

2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,ethyl ester;

2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;

2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;

2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosulfonyl]benzene;

2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;

2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;or

2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene.

Synthesis

The invention provides methods of making the subject compounds andcompositions. In one general embodiment, the methods involve combiningan appropriate sulfonyl chloride (iii) with an appropriate aniline (iv),as outlined in Scheme 1, to yield a sulfonamide (v). The necessarysulfonyl chlorides (iii) can be prepared by sulfonation of theappropriately substituted aromatic compounds (i) with fuming sulfuricacid, followed by treatment with a chlorinating agent, such as PCl₅,POCl₃ and the like, to afford the corresponding sulfonyl chlorides(iii), (Scheme 1). When the sulfonamides contain certain groups, such aschloro or bromo, these groups can be catalytically reduced to produceyet other analogous sulfonamides (vi).

An alternative way of preparing the desired sulfonyl chlorides (iii) isby heating the starting aromatic compounds (i) with chlorosulfonic acidas shown in Scheme 2.

Alternatively, the desired sulfonyl chlorides (iii) are prepared fromtheir corresponding anilines (vii) by dissolving the aniline in anacidic aqueous solution, such as HCl and the like, followed by additionof an aqueous solution of sodium nitrite at a temperature below ambienttemperature, typically between −20 and +5° C. The resulting mixture,containing the desired diazonium salt, is then added to a saturatedsolution of sulfur dioxide in glacial acetic acid containing cuprouschloride, at a temperature between −10 and +10° C., to yield thecorresponding sulfonyl chloride (iii) (see Scheme 3).

The desired sulfonyl chlorides (iii) can also be prepared by oxidationof the respective thiophenols (ix) with chlorine and hydrogen peroxidein acetic acid as shown in Scheme 4.

The sulphinamides described in this patent can be synthesized byreaction of the desired sulfinyl chlorides (xiii) with the appropriateamine (iv), as shown in Scheme 5. The necessary sulfinyl chlorides(xiii) are prepared by metal—halogen exchange reaction on theappropriate aryl bromides (x), chlorides or iodides, with analkyllithium reagent such as butyl-lithium, or with magnesium metal,followed by treatment of the resulting aryl organometallic compounds(xi) with sulfur dioxide affords the lithium sulfinates (xii) that canbe further reacted with thionyl chloride to afford the desired sulfinylchlorides (xiii).

The sulfoxides (xviii) and sulfones (xix) described in this patent canbe prepared by reaction of the desired substituted thiophenols (xv) withthe derivatized benzylic halides (xvi) to yield the correspondingsulfides (xvii), which can be oxidized to the corresponding sulfoxides(xviii) or sulfones (xix) according to Scheme 6. The necessarythiophenols (xv) can be prepared from the starting substituted anilines(vii) by diazotization, followed by treatment with sodium sulfide(Scheme 6).

Alternatively, the thiophenols (xv) can be prepared by treatment of thediazonium salts (viii) with potassium ethyl xanthate, followed bysaponification of the resulting xanthates (xx), as shown in Scheme 7.Other alternate methods for the synthesis of the desired substitutedthiophenols (xv) are described in the chemical literature and are wellknown to individuals versed in the art of organic synthesis.

Sulfoxides (xxiv) and sulfones (xxv) wherein both aromatic rings aredirectly attached to S can be prepared as shown in Scheme 8. Thereaction of fluorobenzene derivatives (xxi) with substituted thiophenols(xxii) provides the diaryl sulfides (xxiii). Oxidation of these sulfidesprovides the desired sulfoxides (xxiv) or sulfones (xxv).

In cases where the desired compounds of Formula I contain one or morebromine, chlorine, or iodide atoms, these can be hydrogenated in thepresence of a catalyst, such as palladium on carbon, to give thecorresponding dehalogenated compounds. This process is outlined inScheme 1. The compounds used as initial starting materials in thisinvention may be purchased from commercial sources or alternatively arereadily synthesized by standard procedures which are well know to thoseof ordinary skill in the art.

Some of the compounds of Formula I may exist as stereoisomers, and theinvention includes all active stereoisomeric forms of these compounds.In the case of optically active isomers, such compounds may be obtainedfrom corresponding optically active precursors using the proceduresdescribed above or by resolving racemic mixtures. The resolution may becarried out using various techniques such as chromatography, repeatedrecrystallization of derived asymmetric salts, or derivatization, whichtechniques are well known to those of ordinary skill in the art.

The compounds of the invention may be labeled in a variety of ways. Forexample, the compounds may contain radioactive isotopes such as, forexample, ³H (tritium) and ¹⁴C (carbon-14). Similarly, the compounds maybe advantageously joined, covalently or noncovalently, directly orthrough a linker molecule, to a wide variety of other compounds, whichmay provide pro-drugs or function as carriers, labels, adjuvents,coactivators, stabilizers, etc. Such labeled and joined compounds arecontemplated within the present invention.

Analysis of Compounds

The subject compounds and compositions were demonstrated to havepharmacological activity in in vitro and in vivo assays, e.g., they arecapable of specifically modulating a cellular physiology to reduce anassociated pathology or provide or enhance a prophylaxis. Compounds andcompositions of a particular embodiment of the invention are capable ofspecifically regulating LDL receptor gene expression. Compounds may beevaluated in vitro for their ability to increase LDL receptor expressionusing western-blot analysis, for example, as described by Tam et al. (J.Biol. Chem. 1991, 266, 16764). Preferred such compounds and compositionsprovide EC_(max) of less than about 50 μM, preferably less than about 5μM, more preferably less than about 0.5 μM, more preferably less thanabout 0.05 μM, and most preferably less than about 0.005 μM in thisassay (see, e.g. Example 28 herein). Established animal models toevaluate hypocholesterolemic effects of compounds are known in the art.For example, compounds disclosed herein are shown to lower cholesterollevels in hamsters fed a high-cholesterol diet, using a protocol similarto that described by Spady et al. (J. Clin. Invest. 1988, 81, 300),Evans et al. (J. Lipid Res. 1994, 35, 1634), and Lin et al (J. Med.Chem. 1995, 38, 277).

Compounds and compositions of a particular embodiment of the inventiondisplay specific toxicity to various types of cells, preferably exertingtheir cytotoxic effects by interacting with cellular tubulin, preferablycovalently and irreversibly. Compounds and compositions may be evaluatedin vitro for their ability to inhibit cell growth, for example, asdescribed by Ahmed et al. (J. Immunol. Methods 1994, 170, 211).Preferred such compounds and compositions provide IC₅₀ of less thanabout 50 μM, preferably less than about 5 μM, more preferably less thanabout 0.5 μM, more preferably less than about 0.05 μM, and mostpreferably less than about 0.005 μM in this assay (see, e.g. Example 28herein). Established animal models to evaluate antiproliferative effectsof compounds are known in the art. For example, compounds can beevaluated for their ability to inhibit the growth of human tumorsgrafted into immunodeficient mice using methodology similar to thatdescribed by Rygaard and Povlsen (Acta Pathol. Microbiol. Scand. 1969,77, 758) and Giovanella and Fogh (Adv. Cancer Res. 1985, 44, 69).

Formulation and Administration of Compounds and PharmaceuticalCompositions

The invention provides methods of using the subject compounds andcompositions to treat disease or provide medicinal prophylaxis, toupregulate LDL receptor gene expression in a cell, to reduce bloodcholesterol concentration in a host, to slow down and/or reduce thegrowth of tumors, etc. These methods generally involve contacting thecell with or administering to the host an effective amount of thesubject compounds or pharmaceutically acceptable compositions.

The compositions and compounds of the invention and the pharmaceuticallyacceptable salts thereof can be administered in any effective way suchas via oral, parenteral or topical routes. Generally, the compounds areadministered in dosages ranging from about 2 mg up to about 2,000 mg perday, although variations will necessarily occur depending on the diseasetarget, the patient, and the route of administration. Preferred dosagesare administered orally in the range of about 0.05 mg/kg to about 20mg/kg, more preferably in the range of about 0.05 mg/kg to about 2mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mgper kg of body weight per day.

In one embodiment, the invention provides the subject compounds combinedwith a pharmaceutically acceptable excipient such as sterile saline orother medium, water, gelatin, an oil, etc. to form pharmaceuticallyacceptable compositions. The compositions and/or compounds may beadministered alone or in combination with any convenient carrier,diluent, etc. and such administration may be provided in single ormultiple dosages. Useful carriers include solid, semi-solid or liquidmedia including water and non-toxic organic solvents.

In another embodiment, the invention provides the subject compounds inthe form of a pro-drug, which can be metabolically converted to thesubject compound by the recipient host. A wide variety of pro-drugformulations are known in the art.

The compositions may be provided in any convenient form includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

The compositions may be advantageously combined and/or used incombination with other hypocholesterolemic or antiproliferativetherapeutic or prophylactic agents, different from the subjectcompounds. In many instances, administration in conjunction with thesubject compositions enhances the efficacy of such agents. Examplaryantiproliferative agents include cyclophosphamide, methotrexate,adriamycin, cisplatin, daunomycin, vincristine, vinblastine,vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea,and mixtures thereof. Exemplary hypocholesterolemic and/or hypolipemicagents include: bile acid sequestrants such as quaternary amines (e.g.cholestyramine and colestipol); nicotinic acid and its derivatives;HMG-CoA reductase inhibitors such as mevastatin, pravastatin, andsimvastatin; gemfibrozil and other fibric acids, such as gemfibrozil,clofibrate, fenofibrate, benzafibrate and cipofibrate; probucol;raloxifene and its derivatives; and mixtures thereof.

The compounds and compositions also find use in a variety of in vitroand in vivo assays, including diagnostic assays. For example, variousallotypic LDL receptor gene expression processes may be distinguished insensitivity assays with the subject compounds and compositions, orpanels thereof. In certain assays and in in vivo distribution studies,it is desirable to used labeled versions of the subject compounds andcompositions, e.g. radioligand displacement assays. Accordingly, theinvention provides the subject compounds and compositions comprising adetectable label, which may be spectroscopic (e.g. fluorescent),radioactive, etc.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

¹H-NMR spectra were recorded on a Varian Gemini 400 MHz NMRspectrometer. Significant peaks are tabulated in the order: number ofprotons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; br s, broad singlet) and coupling constant(s) in Hertz.Electron Ionization (EI) mass spectra were recorded on a Hewlett Packard5989A mass spectrometer. Mass spectrometry results are reported as theratio of mass over charge, followed by the relative abundance of eachion (in parentheses).

Preparation of Synthetic Intermediates

Starting materials for the synthesis of the examples of the presentinvention are available from commercial sources, known in the art, e.g.Organic Syntheses, Coll. Vol. VII; 1990, Jeremiah P. Freeman, ed., JohnWiley & Sons, 508-511; Robson, P., Smith, T. A., Stephens, R., Tatlow,J., J. Chem. Soc., 1963, 3692-3703; and Synthesis of FluoroorganicCompounds; 1985, Knunyants, I. and Yakobson, G., eds., Springer-Verlag,190, and/or exemplified below:

Example A

4-Fluoro-3-nitrophenylsulfonyl Chloride.

2-Fluoronitrobenzene (10.0 g, 70.9 mmol) was added to chlorosulfonicacid (10.0 ml, 150 mmol) at 65° C. After stirring at 85° C. for 18 h,the reaction mixture was cooled to room temperature and poured onto icechips and extracted with CH₂Cl₂ (2×250 ml). The combined organicextracts were washed with saturated NaHCO₃ solution and dried (MgSO₄).Concentration at room temperature and then at 100° C. under high vacuumproduced 2.40 g (14%) of the title compound as a yellow oil. ¹H-NMR(CDCl₃): δ 8.76 (1H, dd, J=2.4, 6.5 Hz), 8.33 (1H, ddd, J=2.4, 3.8, 9.2Hz), 7.61 (1H, t, J=9.2 Hz). MS (EI): 239 (15, M⁺), 204 (100).

Example B

3,5-Dichloro-2,4,6-trifluorophenylsulfonyl Chloride.

1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and chlorosulfonicacid (10.0 ml, 150 mmol) were mixed at ambient temperature under anitrogen atmosphere and the reaction was heated at 80° C. for 24 h. Themixture was then allowed to cool to ambient temperature and was pouredonto 12 g of crushed ice. The product was extracted with diethyl ether,dried over MgSO₄, and evaporated to produce 4.9 g of the title compound,which was used without further purification. MS (EI): 300 (30, M⁺), 298(28), 263 (100), 199 (80).

Example C

2,4,6-Trifluorophenylsulfonyl Chloride.

The title compound was synthesized from 1,3,5-trifluorobenzene by amethod similar to that used in Example B. MS (EI): 230 (20, M⁺), 195(80), 131 (50), 81 (100).

Examples D and E

5-Bromo-2,3,4-trifluorophenylsulfonyl Chloride (Example D) and2-Bromo-3,4,5-trifluorophenylsulfonyl Chloride (Example E).

The title compounds were obtained as a mixture from1-bromo-2,3,4-trifluorobenzene by a method similar to that used inExample B.

Example F

2-Bromo-3,4,5,6-tetrafluorophenylsulfonyl Chloride.

1Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was mixed atambient temperature with 20% fuming sulfuric acid (20 ml). The mixturewas heated at 40° C. for 3 h and at 110° C. for 2 h. The reactionmixture was allowed to cool to ambient temperature and poured onto 12 gof crushed ice. The mixture was acidified dropwise with concentrated HCl(2 ml) until a solid, consisting mostly of2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid was formed. The solid wasfiltered, washed with 12N HCl, and dried under high vacuum to afford 5.3g of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a whitehygroscopic solid that was used without further purification. To thesulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous pentachloride(8.0 g, 38.4 mmol) in small portions, at ambient temperature (Caution:exothermic reaction with significant evolution of HCl). The reaction wasallowed to stir for 20 minutes after the final addition of phosphorouspentachloride. The reaction mixture was then poured onto crushed ice andthe white solid that formed was filtered and dried to afford 2.8 g ofthe title compound, which was used without further purification. MS(EI): 328 (30, M⁺), 293 (70), 229 (30), 148 (100).

Example G

3-Bromo-2,4,5,6-tetrafluorophenylsulfonyl Chloride.

The title compound was synthesized from1-bromo-2,3,4,6-tetrafluorobenzene by a method similar to that used inExample F. MS (EI): 328 (20, M⁺), 293 (70), 229 (50), 148 (100).

Example H

4-Bromo-2,3,5,6-tetrafluorophenylsulfonyl Chloride.

The title compound was synthesized from1-bromo-2,3,5,6-tetrafluorobenzene by a method similar to that used inExample F. MS (EI): 328 (20, M⁺), 293 (70), 229 (50), 148 (100).

Example 1

4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene.

p-Anisidine (760 mg, 6.18 mmol) was added to a solution of4-fluoro-3-nitrophenylsulfonyl chloride (740 mg, 3.09 mmol; Example A)in MeOH (10 ml) at ambient temperature. After stirring at roomtemperature for 15 min, the reaction mixture was concentrated underreduced pressure and the residue was taken up in ethyl acetate andfiltered through a pad of silica gel. Concentration of the filtrate,followed by chromatography, provided 603 mg (60% yield) of the titlecompound. ¹H-NMR (CDCl₃): δ 8.42 (1H, dd, J=2.3, 6.8 Hz), 7.88 (1H, ddd,J=2.4, 4.0, 8.8 Hz), 7.33 (1H, dd, J=8.8, 9.9 Hz), 6.98 (2H, m), 6.81(2H, m), 6.45 (1H, s), 3.77 (3H, s). MS (EI): 326 (11, M⁺), 122 (100).Anal. Calcd. for C₁₃H₁₁FN₂O₅S: C, 47.85; H, 3.40; N, 8.59; S, 9.83.Found: C, 47.68; H, 3.44; N, 8.54; S, 9.88.

Example 2

4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene.

The title compound was prepared in a manner similar to that described inExample 1, by replacing p-anisidine with 3-hydroxy-4-methoxyaniline.¹H-NMR (CDCl₃): δ 8.41 (1H, dd, J=2.4, 6.7 Hz), 7.92 (1H, m), 7.14 (1H,ddd, J=2.4, 4.0, 9.0 Hz), 7.35 (1H, dd, J=9.6, 9.0 Hz), 6.72 (1H, d,J=8.5 Hz), 6.62 (1H, d, J=2.5 Hz), 6.58 (1H, dd, J=2.5, 8.5 Hz), 6.44(1H, s), 5.64 (1H, s), 3.85 (3H, s). Anal. Calcd. for C₁₃H₁₁FN₂O₆S: C,45.62; H, 3.24; N, 8.18; S, 9.37. Found: C, 45.71; H, 3.25; N, 8.17; S,9.29.

Example 3

1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing p-anisidine with 3-hydroxy-4-methoxyaniline andreplacing 4-fluoro-3-nitrophenylsulfonyl chloride with2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F). ¹H-NMR(CDCl₃): δ 7.28 (br s, 1H), 6.69 (m, 3H), 5.72 (s, 1H), 3.82 (s, 3H). MS(EI): 431 (20), 429 (20), 138 (100). Anal. Calcd. for C₁₃H₈BrF₄NO₄S: C,36.30; H, 1.87; N, 3.26; S, 7.45. Found: C, 36.20; H, 1.90; N, 3.31; S,7.39.

Example 4

1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F). ¹H-NMR(CDCl₃): δ 7.23 (1H, br s), 7.07 (2H, dd, J=9.0 and 2.0 Hz), 6.78 (2H,dd, J=9.0 and 2.0 Hz), 3.75 (3H, s). MS (EI): 415/413 (10, M⁺), 122(100). Anal. Calcd. for C₁₃H₈BrF₄NO₃S: C, 37.70; H, 1.95; N, 3.38; S,7.74. Found: C, 37.60; H, 1.92; N, 3.30; S, 7.71.

Example 5

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with3-bromo-2,4,5,6-tetrafluorophenylsulfonyl chloride (Example G). ¹H-NMR(CDCl₃): δ 7.10 (2H, dd, J=9.0 and 2.0 Hz), 7.07 (1H, br s), 6.82 (2H,dd, J=9.0 and 2.0 Hz), 3.77 (3H, s). MS(EI): 415/413 (10, M⁺), 122(100). Anal. Calcd. for C₁₃H₈BrF₄NO₃S: C, 37.70; H, 1.95; N, 3.38; S,7.74. Found: C, 37.66; H, 1.94; N, 3.33; S, 7.67.

Example 6

1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with4-bromo-2,3,5,6-tetrafluorophenylsulfonyl chloride (Example H). ¹H-NMR(CDCl₃): δ 7.16 (1H, br s), 7.11 (2H, dd, J=9.0 and 2.0 Hz), 6.82 (2H,dd, J=9.0 and 2.0 Hz), 3.77 (3H, s). MS(EI) 415/413 (10, M⁺), 122 (100).Anal. Calcd. for C₁₃H₈BrF₄NO₃S: C, 37.70; H, 1.95; N, 3.38; S, 7.74.Found: C, 37.62; H, 1.95; N, 3.34; S, 7.66.

Example 7

1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with4-chloro-2,3,5,6-tetrafluorophenylsulfonyl chloride. ¹H-NMR (CDCl₃): δ7.12 (2H, d, J=9.0 Hz), 6.90 (1H, br s), 6.83 (2H, J=9.0 Hz), 3.78 (3H,s). MS(EI): 369 (20, M⁺), 122 (100).

Example 8

1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example B). ¹H-NMR(CDCl₃): δ 7.09 (2H, d, J=9.0 Hz), 6.85 (1H, br s), 6.82 (2H, d, J=9.0Hz), 3.77 (3H, s). MS (EI): 386 (15, M⁺), 385 (20), 122 (100). Anal.Calcd. for C₁₃H₈Cl₂F₃NO₃S: C, 40.43; H, 2.09; N, 3.63; S, 8.30. Found:C, 40.34; H, 2.06; N, 3.70; S, 8.22.

Example 9

1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing p-anisidine with 3-hydroxy-4-methoxyaniline andreplacing 4-fluoro-3-nitrophenylsulfonyl chloride with3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example B). ¹H-NMR(CDCl₃): δ 6.88 (1H, br s), 6.7-6.8 (3H, m), 5.66 (1H, s), 3.85 (3H, s).MS(EI): 402 (15, M⁺), 401 (20), 138 (100). Anal. Calcd. forC₁₃H₈Cl₂F₃NO₄S: C, 38.83; H, 2.00; N, 3.48; S, 7.97. Found: C, 38.66; H,1.97; N, 3.39; S, 7.86.

Example 10

1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene.

1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene(Example 10) and1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene(Example 11) were prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with amixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D)and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E). The twoisomeric compounds were separated by column chromatography (silica gel;ethyl acetate:hexanes, 1:4). ¹H-NMR (CDCl₃): δ 7.76 (1H, m), 7.04 (2 H;d, J=9.0 Hz), 6.82 (1H, br s), 6.80 (2H, d, J=9.0 Hz), 3.75 (3H, s).MS(EI): 397/395 (20, M⁺), 122 (100). Anal. Calcd. for C₁₃H₉BrF₃NO₃S: C,39.41; H, 2.29; N, 3.54; S, 8.08. Found: C, 39.34; H, 2.23; N, 3.47; S,7.99.

Example 11

1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene.

¹H-NMR (CDCl₃): δ 7.69 (1H, m), 7.08 (1H, br s), 7.03 (2H, dd, J=9.0 and2.0 Hz), 6.76 (2H, dd, J=9.0 and 2.0 Hz), 3.75 (3H, s). MS(EI): 397/395(20, M⁺), 122 (100). Anal. Calcd. for C₁₃H₉BrF₃NO₃S: C, 39.41; H, 2.29;N, 3.54; S, 8.08. Found: C, 39.32; H, 2.31; N, 3.44; S, 7.99.

Example 12

1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene(Example 12) and1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene(Example 13) were prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with amixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D)and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E) andreplacing p anisidine with 3-hydroxy-4-methoxyaniline. The two isomericcompounds were separated by column chromatography (silica gel; ethylacetate:hexanes, 1:4). ¹H-NMR (CDCl₃): δ 7.79 (1H, m), 6.72-6.62 (4H,m), 5.65 (1H, s), 3.85 (3H, s).

Example 13

1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

¹H-NMR (CDCl₃): δ 7.73 (1H, m), 6.94 (1H, br s), 6.72-6.62 (3H, m), 5.63(1H, s), 3.83 (3H, s).

Example 14

2,3,4-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2,3,4-trifluorophenylsulfonyl chloride. ¹H-NMR (CDCl₃): δ 7.51 (1H, m),7.02 (3H, m), 6.78 (2H, dd, J=9.0 and 2.0 Hz), 6.65 (1H, br s), 3.76(3H, s). MS(EI): 317 (20, M⁺), 122 (100). Anal. Calcd. for C₁₃H₁₀F₃NO₃S:C, 49.21; H, 3.18; N, 4.41; S, 10.10. Found: C, 49.10; H, 3.14; N, 4.32;S, 9.99.

Example 15

2,3,4-Trifluoro-1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]ybenzene.

The title compound was prepared in a manner similar to that described inExample 1, by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with3-fluoro-4-methoxyaniline. ¹H-NMR (CDCl₃): δ 7.52 (1H, m), 7.00 (1H, m),6.93 (1H, m), 6.80 (2H, m), 6.70 (1H, br s), 3.80 (3H, s).

Example 16

1-[(3-Chloro-4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with3-chloro-4-methoxyaniline. ¹H-NMR (CDCl₃): δ 7.56 (1H, m), 7.17 (1H, d,J=2.0 Hz), 7.02 (1H, m), 6.98 (1H, dd, J=9.0 and 2.0 Hz), 6.78 (1H, d,J=9.0 Hz), 6.72 (1H, br s), 3.83 (3H, s). MS(EI): 352 (7, M⁺), 351 (20),156 (100). Anal. Calcd. for C₁₃H₉ClF₃NO₃S: C, 44.39; H, 2.58; N, 3.98;S. 9.11. Found: C, 44.31; H, 2.58; N, 3.96; S, 9.08.

Example 17

1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with3-hydroxy-4-methoxyaniline. ¹H-NMR (CDCl₃): δ 7.55 (1H, m), 7.00 (1H,m), 6.70 (2H, m), 6.60 (2H, m), 5.61 (1H, s), 3.83 (3H, s). Anal. Calcd.for C₁₃H₁₀F₃NO₄S: C, 46.85; H, 3.02; N, 4.20; S, 9.62. Found: C, 46.79;H, 3.03; N, 4.24; S, 9.53.

Example 18

2,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with2,4,6-trifluorophenylsulfonyl chloride (Example C). ¹H-NMR (CDCl₃): δ7.08 (2H, dd, J=9.0 and 2.0 Hz), 6.8-6.7 (5H, m), 3.75 (3H, s). Anal.Calcd. for C₁₃H₁₀F₃NO₃S: C, 49.21; H, 3.18; N, 4.41; S, 10.10. Found: C,49.13; H, 3.20; N, 4.39; S, 10.01.

Example 19

2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.

1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzene(250 mg, 0.6 mmol) (Example 5) was dissolved in methanol (25 ml) andplaced in a closed vessel. A catalytic amount of 10% Pd/charcoal (25 mg)was added and the mixture was hydrogenated at 60 psi H₂ for 4 h. Themixture was filtered through celite, the solvent was evaporated and theresidue was purified by chromatography (silica; EtOAc/Hexane, 1:4) toyield 82 mg of the title compound. ¹H-NMR (CDCl₃): δ 7.10 (2H, dd, J=9.0and 2.0 Hz), 6.94 (1H, br s), 6.85 (1H, m). 6.79 (2H, dd, J=9.0 and 2.0Hz), 3.75 (3H, s). MS(EI): 335 (20, M⁺), 122 (100). Anal. Calcd. forC₁₃H₉F₄NO₃S: C, 46.57; H, 2.71; N, 4.18; S, 9.56. Found: C, 46.46; H,2.67; N, 4.17; S, 9.52.

Example 20

2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 19 by replacing1-bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzenewith1-bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene(Example 4). ¹H-NMR (CDCl₃): δ 7.40 (1H, m), 7.05 (2H, dd, J=9.0 and 2.0Hz), 6.80 (2H, dd, J=9.0 and 2.0 Hz), 3.76 (3H, s). MS(EI): 335 (20,M⁺), 122 (100). Anal. Calcd. for C₁₃H₉F₄NO₃S: C, 46.57; H, 2.71; N,4.18; S, 9.56. Found: C, 46.44; H, 2.67; N, 4.13; S, 9.47.

Example 21

2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 19 by replacing1-bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzenewith1-bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene(Example 3). ¹H-NMR (CDCl₃): δ 7.43 (1H, m), 6.80 (1H, br s), 6.73-6.60(3H, m), 5.67 (1H, s), 3.84 (3H, s). MS(EI): 351(20, M⁺), 138 (100).Anal. Calcd. for C₁₃H₉F₄NO₄S: C, 44.45; H, 2.58; N, 3.99; S, 9.13.Found: C, 44.39; H, 2.59; N, 3.94; S, 9.24.

Example 22

3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 19 by replacing1-bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzenewith 1-bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene(Example 11). ¹H-NMR (CDCl₃): δ 7.35 (2H, t, J=6.0 Hz), 7.00 (2H, d,J=9.0 Hz), 6.81 (2H, d, J=9.0 Hz), 3.78 (3H, s). MS(EI) 317 (20, M⁺),122 (100). Anal. Calcd. for C₁₃H₁₀F₃NO₃S: C, 49.21; H, 3.18; N, 4.41; S,10.10. Found: C, 49.09; H, 3.15; N, 4.37; S, 10.03.

Example 23

3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene.

The title compound was prepared in a manner similar to that described inExample 19 by replacing1-bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzenewith1-bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene(Example 13). ¹H-NMR (CDCl₃): δ 7.38 (2H, t, J=6.0 Hz), 6.74 (1H, d,J=9.0 Hz), 6.64 (1H, d, J=2.0 Hz), 6.58 (1H, dd, J=9.0 and 2.0 Hz), 5.64(1H, s), 3.88 (3H, s). Anal. Calcd. for C₁₃H₁₀F₃NO₄S: C, 46.85; H, 3.02;N, 4.20; S, 9.62. Found: C, 46.75; H, 3.01; N, 4.20; S, 9.56.

Example 24

4-Methoxybenzyl Pentafluorophenyl Sulfone.

To a solution of 4-methoxybenzylbromide (2.00 g, 9.95 mmol) in DMF (20ml) at room temperature was added potassium carbonate (2.07 g, 15.0mmol) followed by pentafluorothiophenol (1.33 ml, 9.97 mmol). Afterstirring at room temperature for 1 h, the reaction mixture was pouredonto water and extracted with diethyl ether. The combined organicextracts were washed with 1 M NaOH, dried and concentrated to give awhite solid which was used directly in the next step. The sulfide (1.11g, 3.47 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0°C. m-chloroperbenzoic acid, MCPBA, (1.20 g, 6.95 mmol) was added and theresulting mixture stirred at room temperature for 2 h. The reactionmixture was poured onto 1 M NaOH (50 ml) and extracted withdichloromethane (3×25 ml). The combined organic extracts were washedwith brine, dried (MgSO₄),concentrated and flash chromatographed(25:25:1, 20:20:3/hexanes:dichloromethane:ethyl acetate) to provide 413mg (34%) of the title compound as a white solid. ¹H NMR (CDCl₃): d7.18-7.22 (2H, m), 6.85-6.80 (2H, m), 4.48 (2H, s), 3.78 (3H, s). MS(EI): m/z 352 (2, M⁺), 121 (100). Anal Calcd. for C₁₄H₉F₅O₃S: C, 47.73;H, 2.58; S, 9.10. Found: C, 47.88; H, 2.66; S, 8.97.

Example 25

1-[(3,4-Dimethoxyphenyl)aminosulfonyl]-3-fluoro-5-nitro-4-trifluoromethoxy-benzene.

3,4-Dimethoxyaniline (1.53 g, 10 mmol) is added to a solution of3-fluoro-5-nitro-4-trifluoromethoxyphenylsulfonyl chloride (2.87 g, 12mmol) in MeOH (20 ml) at ambient temperature. After stirring at roomtemperature for 15 min, the reaction mixture is concentrated underreduced pressure and the residue is taken up in ethyl acetate andfiltered through a pad of silica gel. Concentration of the filtrate,followed by chromatography, provides the title compound.

Example 26

4-Azido-1-[(4-dimethylamino-3-methoxyphenyl)aminosulfonyl]-2,3,5,6-tetrafluoro-benzene.

4-Dimethylamino-3-methoxyaniline (1.66 g, 10 mmol) is added to asolution of 4-azido-2,3,5,6-tetrafluorophenylsulfonyl chloride (3.47 g,12 mmol) in MeOH (20 ml) at ambient temperature. After stirring at roomtemperature for 15 min, the reaction mixture is concentrated underreduced pressure and the residue is taken up in ethyl acetate andfiltered through a pad of silica gel. Concentration of the filtrate,followed by chromatography, provides the title compound.

Example 27

3,5-dinitro-1-[(3,4-methylenedioxyphenyl)aminosulfonyl]-4-(trifluomethylsulfonamido)benzene

3,4-Methylenedioxyaniline (1.37 g, 10 mmol) is added to a solution of3,5-dinitro-4-(trifluoromethylsulfonamido)phenyisulfonyl chloride (4.96g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirring atroom temperature for 15 min, the reaction mixture is concentrated underreduced pressure and the residue is taken up in ethyl acetate andfiltered through a pad of silica gel. Concentration of the filtrate,followed by chromatography, provides the title compound.

Example 28

Assessment of Biological Activity.

Compounds were evaluated for their ability to inhibit in vitro thegrowth of HeLa cells, an immortal cell line derived from a humancervical carcinoma commonly used to evaluate the cytotoxicity ofpotential therapeutic agents. The following data reflect thecytotoxicity of selected examples of the present invention. The valuesgiven represent the concentration of test compound required to inhibitby 50% the uptake of Alamar Blue (Biosource International, Camarillo,Calif.) by HeLA cell cultures, which correlates directly with theoverall levels of cellular metabolism in the culture, and is generallyaccepted as an appropriate marker of cell growth. The test was conductedaccording to the method of Ahmed et al. (J. Immunol. Methods 1994, 170,211). The following selected examples display potent cytotoxic activityin this assay, with IC₅₀ values ranging from 0.05 μM to 5.0 μM.

Compound IC50 (μM) Example 2 0.15 Example 3 0.05 Example 4 0.15 Example5 0.15 Example 6 5.0 Example 7 1.5 Example 8 0.15 Example 9 0.05 Example10 0.5 Example 11 0.5 Example 17 1.5 Example 19 5.0 Example 20 0.5Example 21 0.15 Example 22 5.0 Example 23 1.5 Example 24 5.0

Certain compounds were evaluated for their ability to increase LDLreceptor expression in HepG2 cells using western-blot analysis asdescribed by Tam et al., (J. Biol. Chem., 1991, 266, 16764). The datapresented (EC_(max)) reflect the minimum concentration at which amaximal induction of LDL receptor levels was observed for each compound.In all cases, the level of induction was greater than that observedunder lipid-free conditions (activated system) in the absence of thetest compounds.

Compound EC_(max) (μm) Example 1 5 Example 2 1.5 Example 3 0.15 Example4 0.5 Example 5 0.5 Example 6 50 Example 7 50 Example 8 0.5 Example 90.15 Example 10 1.5 Example 11 1.5 Example 19 15 Example 20 1.5 Example21 0.5 Example 22 5 Example 24 1.5

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: n is 2; R¹ is amember selected from the group consisting of hydrogen, (C1-C6) alkyl,halogen, OCF₃, CF₃, NO₂, CN, and CO₂—R⁸; R² is a member selected fromthe group consisting of NO₂, CN, CO₂—R⁸ and SO₂—R⁸; R³ is a memberselected from the group consisting of halogen and OCF₃; R⁴ is a memberselected from the group consisting of hydrogen, halogen, OCF₃, CF₃, NO₂,CN, and CO₂—R⁸; R⁵ is a member selected from the group consisting ofhydrogen, (C1-C6) alkyl, halogen, OCF₃, CF₃, NO₂, CN, and CO₂—R⁸; Y isN(R⁹); wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, (C1-C6) alkyl and (C2-C6) heteroalkyl; R⁸ isselected from the group consisting of (C1-C6) alkyl and (C2-C6)heteroalkyl; and R⁹ is selected from the group consisting of hydrogen,substituted or unsubstituted (C1-C10)alkyl, substituted or unsubstituted(C3-C6)alkenyl, subsituted or unsubstituted (C2-C6)heteroalkyl,substituted or unsubstituted (C3-C6)heteroalkenyl, substituted orunsubstituted (C3-C6)alkynyl, substituted or unsubstituted(C3-C8)cycloalkyl; and Ar is a substituted or unsubstituted phenylgroup, wherein said substituents are independently selected from thegroup consisting of OH, halogen, NH₂, NH(C1-C6)alkyl, N((C1-C6)alkyl)₂,(C1-C6) alkyl, and (C1-C6)alkoxy.
 2. The compound of claim 1, wherein R³is halogen.
 3. The compound of claim 2, wherein R⁴ is selected from thegroup consisting of hydrogen, F, Cl, Br, OCF₃, CF₃, NO₂, and CN.
 4. Thecompound of claim 3, wherein R³ is F, Cl or Br.
 5. The compound of claim4, wherein R³ is F.
 6. The compound of claim 5, wherein R² is selectedfrom the group consisting of NO₂, CN, and CO₂—R⁸.
 7. The compound ofclaim 6, wherein R⁴ is selected from the group consisting of hydrogen,F, Cl, Br, OCF₃ and CF₃.
 8. The compound of claim 4, wherein R³ is Cl.9. The compound of claim 8, wherein R² is selected from NO₂, CN, andCO₂—R⁸.
 10. The compound of claim 9, wherein R⁴ is selected from thegroup consisting of are independently selected from F, Cl, Br, OCF₃. 11.The compound of claim 4, wherein R³ is Br.
 12. The compound of claim 11,wherein R² is selected from NO₂, CN, and CO₂—R⁸.
 13. The compound ofclaim 12, wherein R⁴ is a member selected from the group consisting ofF, Cl, Br, OCF₃ and CF₃.
 14. The compound of claim 11, wherein R³ isOCF₃.
 15. The compound of claim 14, wherein R² is selected from NO₂, CNand CO₂—R⁸.
 16. The compound of claim 15, wherein R² and R⁴ areindependently selected from F, Cl, Br, OCF₃ and CF₃.